ε-N-acetylation of lysine residues is one of the most frequently occurring posttranslational modifications in proteins (Choudhary et al., 2009) and has broad relevance to cellular signalling and disease biology. Lysine acetylation in histones is abundant in large macromolecular complexes that are involved in chromatin remodeling, DNA damage repair, and cell-cycle control (Choudhary et al., 2009). Targeting chromatin modifying enzymes that control cellular acetylation levels, the so-called epigenetic ‘writers’ (histone acetyltransferases, HATs) and ‘erasers’ (histone deacetylases, HDACs) has been an area of extensive research in drug development, but modulating the ‘readers’ (bromodomains) that recognize acetylation sites has not been widely reported until recently (Nicodeme et al 2010, Filippakopoulos et al 2010). Bromodomains (BRDs) are a diverse family of evolutionary conserved protein-interaction modules that specifically recognize protein motifs that contain acetyl-lysine modification. The extra-terminal (BET) bromodomain subfamily consists of BRD2, BRD3, BRD4 and BRDT, shares a common domain architecture featuring two amino-terminal bromodomains with high levels of sequence homology, and a carboxy-terminal domain. Recent research has validated targeting BET bromodomains to treat a number of cancers [Filippakopoulos 2010, Delmore 2011, Zuber 2011], atherosclerosis [Chung 2011, Mirguet 2012, inflammation [Nicodeme 2010] and HIV infection [Banerjee 2012].
The MYC transcription factor is a master regulator of diverse cellular functions and has long been validated as a compelling therapeutic target for a range of human cancers, yet strategies to modulate the function of the Myc oncoprotein have not been discovered. Recently, two selective inhibitors of the BET family members (with little activity against bromodomains outside of the BET family), JQ1 and IBET-151, have been shown to potently downregulate MYC protein and MYC target gene transcription. In a MYC-dependent manner, JQ1 and IBET-151 potently inhibit in vitro and in vivo tumor growth of multiple myeloma, a variety of leukemia and lymphoma cell lines as well as primary leukemia patient samples (Delmore 2011, Mertz, 2011, Zuber 2011, Herrmann 2010, Dawson, 2011). BET bromodomain inhibitors could also be useful in treating other cancers that depend on MYC function, such as neuroblastoma with MYCN amplification and other solid tumors with c-MYC overexpression, in addition, JQ1 has also be shown to have antiproliferative effects in an incurable subtype of human squamous carcinoma, known as NUT midline carcinoma (NMC). NMC is a genetically defined cancer with a chromosomal rearrangement involving t(15,19) that leads to expression of the tandem N-terminal bromodomains of BRD4 or BRD3 as an in-frame chimaera with the NUT (nuclear protein in testis) protein. JQ1 treatment leads to terminal differentiation, cell cycle arrest and apoptosis in NMC cell lines, and significant reduction of tumour growth in patient-derived xenograft models [Filippakopoulos 2010]. In summary, BET bromodomain inhibitors can be useful in the treatment of a variety of human cancers.
A BET bromodomain inhibitor, IBET, has been reported to suppress several crucial pro-inflammatory cytokines and chemokines by displacing BET proteins from the promoter of its inflammatory genses. IBET demonstrates anti-inflammatory effect and protects animals from endotoxin-induced death in a mouse sepsis model (Nicodeme 2010). These studies suggest that BET bromodomain inhibitors could be useful as immomodulating drugs.
Apolipoprotein A1 (ApoA1) upregulation is associated with protection from atherosclerosis progression and with anti-inflammatory effects (Nicholls 2012). BET bromodomain inhibitors have been discovered to increase ApoA1 expression. BET inhibitors are promising approaches for the development of new therapies for atherosclerosis.
The persistence of latent HIV-1 is a major challenge in efforts to eradicate infection. JQ1 has been reported to reactivate HIV virus in models of latent T cell infection and latent monocyte infection (Banerjee 2012, Li 2003). Combination therapies using BET bromodomain inhibitors to reactive latent HIV-1 virus can provide an opportunity to cure HIV-1 infection. Other BET bromodomain inhibitors are also known. See, for example, WO2012151512, WO2012143436, WO2012075383, WO2011161031, WO2011143669, WO2011143657, WO2011054848, WO2011054846, WO2011054845, WO2011054844, WO2011054843, WO WO2011054841, WO2011054553, WO2009084693, and WO2006032470. Certain 3,5-dimethylisoxazoles have been identified as BRD4 inhibitors (David S. Hewings 2011).